sign in sign up
<<
Home , Rickets, Vitamin D deficiency

CLINICAL REPORT

Guidance for the Clinician in Rendering Prevention of and D Pediatric Care Deficiency in Infants, Children, and Adolescents

Carol L. Wagner, MD, Frank R. Greer, MD, and the Section on and Committee on Nutrition

ABSTRACT Rickets in infants attributable to inadequate intake and decreased exposure to continues to be reported in the United States. There are www..org/cgi/doi/10.1542/ peds.2008-1862 also concerns for vitamin D deficiency in older children and adolescents. Because there are limited natural dietary sources of vitamin D and adequate doi:10.1542/peds.2008-1862 sunshine exposure for the cutaneous synthesis of vitamin D is not easily All clinical reports from the American Academy of Pediatrics automatically expire determined for a given individual and may increase the risk of skin , the 5 years after publication unless reaffirmed, recommendations to ensure adequate vitamin D status have been revised to revised, or retired at or before that time. include all infants, including those who are exclusively breastfed and older The guidance in this report does not children and adolescents. It is now recommended that all infants and children, indicate an exclusive course of treatment including adolescents, have a minimum daily intake of 400 IU of vitamin D or serve as a standard of medical care. Variations, taking into account individual beginning soon after birth. The current recommendation replaces the previous circumstances, may be appropriate. recommendation of a minimum daily intake of 200 IU/day of vitamin D Key Words supplementation beginning in the first 2 months after birth and continuing vitamin D, vitamin D deficiency, rickets, through adolescence. These revised guidelines for vitamin D intake for healthy vitamin D requirements, infants, children, infants, children, and adolescents are based on evidence from new clinical trials adolescents, 25-hydroxyvitamin D, vitamin D supplements and the historical precedence of safely giving 400 IU of vitamin D per day in the Abbreviations pediatric and adolescent population. New evidence supports a potential role for AAP—American Academy of Pediatrics vitamin D in maintaining innate immunity and preventing diseases such as 25-OH-D—25-hydroxyvitamin D diabetes and cancer. The new data may eventually refine what constitutes 1,25-OH2-D—1,25-dihydroxyvitamin D vitamin D sufficiency or deficiency. Pediatrics 2008;122:1142–1152 PTH— PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2008 by the American Academy of Pediatrics INTRODUCTION This statement is intended to replace a 2003 clinical report from the American Academy of Pediatrics (AAP),1 which recommended a daily intake of 200 IU/day of vitamin D for all infants (beginning in the first 2 months after birth), children, and adolescents. The new recommended daily intake of vitamin D is 400 IU/day for all infants, children, and adolescents beginning in the first few days of life.

BACKGROUND Rickets attributable to vitamin D deficiency is known to be a condition that is preventable with adequate nutritional intake of vitamin D.2–6 Despite this knowledge, cases of rickets in infants attributable to inadequate vitamin D intake and decreased exposure to sunlight continue to be reported in the United States and other Western countries, particularly with exclusively breastfed infants and infants with darker skin pigmentation.4,7–14 Rickets, however, is not limited to infancy and early childhood, as evidenced by cases of rickets caused by nutritional vitamin D deficiency being reported in adolescents.15 Rickets is an example of extreme vitamin D deficiency, with a peak incidence between 3 and 18 months of age. A state of deficiency occurs months before rickets is obvious on physical examination, and the deficiency state may also present with hypocalcemic seizures,16–18 growth failure, lethargy, irritability, and a predisposition to respiratory infections during infancy.16–22 In a retrospective review of children presenting with vitamin D deficiency in the ,16 there were 2 types of presentations. The first was symptomatic (including seizures) occurring during periods of rapid growth, with increased metabolic demands, long before any physical findings or radiologic evidence of vitamin D deficiency occurred. The second clinical presentation was that of a more chronic disease, with rickets and/or decreased mineralization and either normocalcemia or asymptomatic hypocalce-

1142 AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on October 2, 2021 TABLE 1 Vitamin D Deficiency: Stages and Clinical Signs 1. Stages of vitamin D deficiency Stage I

25-OH-D level decreases, resulting in hypocalcemia and euphosphatemia; 1,25-OH2-D may increase or remain unchanged Stage II 25-OH-D level continues to decrease; PTH acts to maintain through demineralization of bone; the patient remains eucalcemic and hypophosphatemic and has a slight increase in the skeletal level Stage III Severe 25-OH-D deficiency with hypocalcemia, , and increased alkaline phosphatase; have overt signs of demineralization 2. Clinical signs of vitamin D deficiency ● Dietary calcium absorption from the gut decreases from 30%–40% to 10%–15% when there is vitamin D deficiency ● Low concentrations of 25-OH-D trigger the release of PTH in older infants, children, and adolescents in an inverse relationship not typically seen with young infants; the increase in PTH mediates the mobilization of calcium from bone, resulting in a reduction of bone mass; as bone mass decreases, the risk of fractures increases Rickets Enlargement of the skull, joints of long bones, and rib cage; curvature of spine and femurs; generalized muscle weakness and osteopenia Abnormal immune function with greater susceptibility to acute infections and other long-latency disease states (see below) 3. Potential latent disease processes associated with vitamin D deficiency ● Dysfunction of the innate immune system is noted with vitamin D deficiency Immunomodulatory actions may include • Potent stimulator of innate immune system acting through Toll-like receptors on monocytes and macrophages • Decrease threshold for long-latency diseases such as (including leukemia and colon, prostate, and breast cancers), psoriasis, diabetes mellitus, and autoimmune diseases (eg, multiple sclerosis, , systemic erythematosis)

mia. (For a more complete review of nutritional rickets nificant amounts only in fatty fish and certain fish oils, and its management, please refer to the recent publica- liver and fat from aquatic mammals, and egg yolks of tion in and Metabolism Clinics of North Amer- chickens fed vitamin D.32 In adults, new evidence sug- ica on the topic.23) gests that vitamin D plays a vital role in maintaining 33 There are 2 forms of vitamin D: D2 (, innate immunity and has been implicated in the pre- 34,35 synthesized by plants) and D3 (, synthe- vention of certain disease states including infection, sized by mammals). The main source of vitamin D for autoimmune diseases (multiple sclerosis,28,33,36,37 rheu- 38 humans is vitamin D3 through its synthesis in the skin matoid arthritis ), some forms of cancer (breast, ovar- when UV-B in the range of 290 to 315 nm converts ian, colorectal, prostate),24,30,39–42 and 43–45 7-dehydrocholesterol into previtamin D3. Through the mellitus. Results from prospective observational heat of the skin, previtamin D3 is further transformed studies also suggest that vitamin D supplements in in- into vitamin D3, which then binds to the vitamin fancy and early childhood may decrease the incidence of D–binding protein and is transported to the liver and mellitus.46–50 converted to 25-hydroxyvitamin D (25-OH-D) by the ac- tion of 25-hydroxylase. 25-OH-D, the nutritional indicator RECOMMENDED DAILY INTAKE OF VITAMIN D FOR INFANTS of vitamin D, undergoes a second in the AND CHILDREN kidney and other tissues to become 1,25-dihydroxyvitamin In partnership with the Institute of Medicine, the Na- D (1,25-OH2-D). Vitamin D is an important prehormone tional Academy of Sciences Panel for Vitamin D recom- with active metabolites (25-OH-D and 1,25-OH2-D) that mended in 1997 a daily intake of 200 IU vitamin D to are involved in many metabolic processes beyond bone prevent vitamin D deficiency in normal infants, children integrity and calcium homeostasis.24 More-detailed reviews and adolescents.51 This recommendation was endorsed of vitamin D physiology and metabolism are available from by the AAP in a previous clinical report.1 The National Hathcock et al,25 Holick,26 Webb,27 and Misra et al.23 Academy of Sciences guidelines for infants were based It is important to note that measuring the concentra- on data primarily from the United States, Norway, and tion of 1,25-OH2-D instead of 25-OH-D for assessment of China, which showed that an intake of at least 200 vitamin D status can lead to erroneous conclusions, be- IU/day of vitamin D prevented physical signs of vitamin cause 1,25-OH2-D concentrations will be normal or even D deficiency and maintained the concentration of 25- elevated in the face of vitamin D deficiency as a result of OH-D at or above 27.5 nmol/L (11 ng/mL).† These secondary (see Table 1). Preven- recommendations were made despite 50 years of clinical tion of vitamin D deficiency and achieving adequate experience demonstrating that 400 IU of vitamin D (the intake of vitamin D and calcium throughout childhood concentration measured in a teaspoon of ) may reduce the risk of as well as other not only prevented rickets but also treated it.52–55 Primar- long-latency disease processes that have been associated ily on the basis of new information in adults linking with vitamin D–deficiency states in adults.28–31 The presence of vitamin D as a natural ingredient in †Universal units of measure for 25-OH-D and 1,25-OH2-D are nmol/L. Conversion to ng/mL is food in most diets is limited, occurring in relatively sig- made by dividing the value expressed in nmol/L by 2.496. Thus, 80 nmol/L becomes 32 ng/mL.

PEDIATRICS Volume 122, Number 5, November 2008 1143 Downloaded from www.aappublications.org/news by guest on October 2, 2021 other biomarkers (parathyroid hormone [PTH], insulin and the risks of various skin cancers.100 Indirect epi- resistance, bone mineralization, and calcium absorption demiologic evidence now suggests that the age at studies) to vitamin D deficiency, there is a growing con- which direct sunlight exposure is initiated is even cern that the previous recommendation of 200 IU/day as more important than the total sunlight exposure over an adequate intake of vitamin D is not sufficient, even a lifetime in determining the risk of .101–105 for infants and children.53,56–61 Among dermatologists, there is active discussion This new information has resulted in defining vita- about the risks and potential benefits of sun exposure min D deficiency in adults as a 25-OH-D concentration and/or oral vitamin D supplementation97,99,106; how- of Ͻ50 nmol/L and vitamin D insufficiency as a 25- ever, the vast majority would agree with the current OH-D concentration of 50 to 80 nmol/L.25,26,62–67 At the AAP guidelines for decreasing sunlight exposure, present time, however, consensus has not been which include the advice that infants younger than 6 reached with regard to the concentration of 25-OH-D months should be kept out of direct sunlight. Al- to define vitamin D insufficiency for infants and chil- though the AAP encourages physical activity and time dren.66–69 Although there may not be a precise defini- spent outdoors, children’s activities that minimize tion of what constitutes vitamin D insufficiency in sunlight exposure are preferred, and when outdoors, infants and children, it is known that 200 IU/day of protective clothing as well as should be vitamin D will not maintain 25-OH-D concentrations used.105 In following these guidelines, vitamin D sup- at Ͼ50 nmol/L in infants, the concentration attributed plements during infancy, childhood, and adolescence to vitamin D sufficiency in adults.62,67,70–74 On the other are necessary. hand, 400 IU/day of vitamin D has been shown to maintain serum 25-OH-D concentrations at Ͼ50 PREGNANCY, VITAMIN D, AND THE FETUS nmol/L in exclusively breastfed infants.73 It is also of The Institute of Medicine in 199751 and a Cochrane note that liquid and vitamin D–only prepa- review in 2002107 concluded that there are few data rations available in the United States conveniently available regarding maternal vitamin D requirements supply 400 IU/day, not 200 IU/day, in either drop or during pregnancy, despite the fact that maternal vitamin milliliter preparations. D concentrations largely determine the vitamin D status of the fetus and newborn infant. With restricted vitamin SUNLIGHT EXPOSURE AND VITAMIN D D intake and sunlight exposure, maternal deficiency Historically, the main source of vitamin D has been via may occur, as has been documented in a number of synthesis in the skin from cholesterol after exposure to studies.107–113 UV-B light. Full-body exposure during summer months Recent work has demonstrated that in men and non- for 10 to 15 minutes in an adult with lighter pigmenta- pregnant women, oral vitamin D intake over a 4- to tion will generate between 10 000 and 20 000 IU of 5-month period will increase circulating 25-OH-D con- vitamin D3 within 24 hours; individuals with darker centrations by approximately 0.70 nmol/L for every 40 pigmentation require 5 to 10 times more exposure to IU of vitamin D ingested,114,115 which is consistent with 75–78 generate similar amounts of vitamin D3. The amount earlier work performed in pregnant women. In those of UV exposure available for the synthesis of vitamin D studies, as predicted by vitamin D kinetics, supplements depends on many factors other than just time spent of 1000 IU/day of vitamin D to pregnant women resulted outdoors. These factors include the amount of skin pig- in a 12.5 to 15.0 nmol/L increase in circulating 25-OH-D mentation, body mass, degree of latitude, season, the concentrations in both maternal and cord serum com- amount of cloud cover, the extent of air pollution, the pared with nonsupplemented controls.108–110 Maternal amount of skin exposed, and the extent of UV protec- 25-OH-D concentrations ranged from a mean of approx- tion, including clothing and sunscreens.56,77,79–81 The In- imately 25 nmol/L at baseline to 65 Ϯ 17.5 nmol/L at door Air Quality Act of 1989 reported that Americans 230 days of gestation in the group of women who re- spent an average of 93% of their time indoors,82 sup- ceived 1000 IU of vitamin D per day during the last porting the higher prevalence of lower 25-OH-D con- trimester. In comparison, 25-OH-D concentrations centrations among adult Americans.83,84 More recently, were 32.5 Ϯ 20.0 nmol/L in the unsupplemented vitamin D deficiency (as defined by concentrations of control group. These data suggest that doses exceeding 25-OH-D Ͻ 25 nmol/L) among school-aged children and 1000 IU of vitamin D per day are necessary to achieve adolescents has been reported, reflecting modern-day 25-OH-D concentrations of Ͼ50 nmol/L in pregnant lifestyle changes.3,6,9,58,85–96 women.108–115 The significance of these findings for The multitude of factors that affect vitamin D syn- those who care for the pediatric population is that thesis by the skin,27 the most important of which is when a woman who has vitamin D deficiency gives degree of skin pigmentation, make it difficult to de- birth, her neonate also will be deficient. termine what is adequate sunshine exposure for any It is important to note that women with increased given infant or child.97–99 Furthermore, to limit expo- skin pigmentation or who have little exposure of their sure to UV light, the Centers for Disease Control and skin to sunlight are at a greater risk of vitamin D defi- Prevention, with the support of many organizations ciency and may need additional vitamin D supplements, including the AAP and the American Cancer Society, especially during pregnancy and lactation.71 In a study launched a major public health campaign in 1998 to by van der Meer et al,116 Ͼ50% of pregnant women with increase public awareness about sunlight exposure darker pigmentation in the Netherlands were vitamin D

1144 AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on October 2, 2021 deficient, as defined by a 25-OH-D concentration of Ͻ25 D content of her ranges from Ͻ25 to 78 IU/L.73,74,126–129 nmol/L. Infants who are exclusively breastfed but who do not Studies in human subjects have shown a strong rela- receive supplemental vitamin D or adequate sunlight tionship between maternal and fetal circulating (cord exposure are at increased risk of developing vitamin D blood) 25-OH-D concentrations.117–120 With severe ma- deficiency and/or rickets.7,10–12,14,18,81,130 Infants with ternal vitamin D deficiency, the fetus may rarely develop darker pigmentation are at greater risk of vitamin D rickets in utero and manifest this deficiency at birth.71 deficiency,131 a fact explained by the greater risk of de- Supplementation with 400 IU of vitamin D per day ficiency at birth132 and the decreased vitamin D content during the last trimester of pregnancy has minimal effect in milk from women who themselves are deficient.127 on circulating 25-OH-D concentrations in the mother A small number of studies have examined the effect and her infant at term.112 An unsupplemented infant of higher maternal supplements of vitamin D on the born to a vitamin D–deficient mother will reach a state 25-OH-D concentrations in breastfed infants. Supple- of deficiency more quickly than an infant whose mother ments of 1000 to 2000 IU of vitamin D per day to nursing was replete during pregnancy.71 mothers have little effect on the breastfeeding infant’s Adequate nutritional vitamin D status during preg- vitamin D status as measured by infant 25-OH-D con- nancy is important for fetal skeletal development, centrations.81,133,134 In 2 recent pilot studies that involved tooth enamel formation, and perhaps general fetal lactating women supplemented with high-dose vitamin growth and development.121 There is some evidence D (up to 6400 IU/day), the vitamin D content of the that the vitamin D status of the mother has long-term mothers’ milk increased to concentrations as high as 873 effects on her infant. In a recent Canadian study by IU/L without any evidence of maternal vitamin D tox- Mannion et al comparing growth parameters in new- icity.73,74 The 25-OH-D concentrations in breastfed in- born infants with the maternal intakes of milk and fants of mothers who received 6400 IU/day of vitamin D vitamin D during pregnancy, investigators found an increased from a mean concentration of 32 to 115 association between vitamin D intake during preg- nmol/L. These results compared favorably with infants nancy and birth weight but not infant head circum- receiving 300 to 400 IU of vitamin D per day, whose ference or length at birth.122 With every additional 40 25-OH-D concentrations increased from a mean of 35 to IU of maternal vitamin D intake, there was an associ- 107 nmol/L. Although vitamin D concentrations can be ated 11-g increase in birth weight. Another study of increased in milk of lactating women by using large the intrauterine effect of maternal vitamin D status vitamin D supplements, such high-dose supplementa- revealed a significant association between umbilical tion studies in lactating women must be validated and cord 25-OH-D concentrations and head circumference demonstrated to be safe in larger, more representative at 3 and 6 months’ postnatal age that persisted after populations of women across the United States. Recom- adjustment for confounding factors.109,111 A study per- mendations to universally supplement breastfeeding formed in the United Kingdom during the 1990s mothers with high-dose vitamin D cannot be made at demonstrated that higher maternal vitamin D status this time. Therefore, supplements given to the infant are during pregnancy was associated with improved bone- necessary. content and bone mass in children at 9 years of age.123 VITAMIN D SUPPLEMENTATION FOR BREASTFEEDING Given the growing evidence that adequate maternal INFANTS vitamin D status is essential during pregnancy, not only Although it is clear and incontrovertible that human for maternal well-being but also for fetal develop- milk is the best nutritive substance for infants during the ment,71,122,124,125 health care professionals who provide first year,135–137 there has been concern about the ade- obstetric care should consider assessing maternal vita- quacy of human milk in providing vitamin D.70,138 As min D status by measuring the 25-OH-D concentrations such, the AAP published its 2003 vitamin D supplemen- of pregnant women. On an individual basis, a mother tation statement,1 recommending that all breastfed in- should be supplemented with adequate amounts of vi- fants start to receive 200 IU of vitamin D per day within tamin D3 to ensure that her 25-OH-D levels are in a the first 2 months after delivery. sufficient range (Ͼ80 nmol/L).25,26,64,66,67 The knowledge With improved understanding of the detrimental ef- that prenatal vitamins containing 400 IU of vitamin D3 fects of insufficient vitamin D status before the appear- have little effect on circulating maternal 25-OH-D con- ance of rickets, studies in North America are continuing centrations, especially during the winter months, should to examine the vitamin D status of children and appro- be imparted to all health care professionals involved in priate 25-OH-D serum concentrations. A 2003 report of the care of pregnant women.26,64,71,115 serum 25-OH-D status in healthy 6- to 23-month-old children in Alaska revealed that 11% had concentrations THE EFFECT OF MATERNAL VITAMIN D SUPPLEMENTATION of Ͻ37 nmol/L and 20% had concentrations of 37 to 62 DURING LACTATION ON THE VITAMIN D STATUS OF THE nmol/L.139,140 Thirty percent of the infants were still BREASTFED INFANT breastfeeding, and these infants were more likely to The vitamin D content of human milk (parental vitamin have serum 25-OH-D concentrations of Ͻ37 nmol/L. D compound plus 25-OH-D) is related to the lactating After this study, the Alaskan Special Supplemental Nu- mother’s vitamin D status.71–74,126 In a lactating mother trition Program for Women, Infants, and Children (WIC) supplemented with 400 IU/day of vitamin D, the vitamin began an initiative to actively identify breastfeeding chil-

PEDIATRICS Volume 122, Number 5, November 2008 1145 Downloaded from www.aappublications.org/news by guest on October 2, 2021 TABLE 2 Oral Vitamin D Preparations Currently Available in the United States (in Alphabetical Order) Preparationa Dosage Bio-D-Mulsion (Biotics Research Laboratory, Rosenberg, TX; 1 drop contains 400 IUb; also comes in a preparation of 2000 IU per dropb; www.bioticsresearch.com) corn oil preparation Carlson Laboratories (Arlington Heights, IL; www.carlsonlabs.com) 1 gel cap contains 400 IU; also comes in 2000-IU and 4000-IU gel caps and in single-drop preparations of 400-IU, 1000-IU, and 2000-IUb; safflower oil preparation Just D (Sunlight Vitamins Inc ͓Distributed by UnitDrugCo, Centennial, CO͔; 1 mL contains 400 IU; corn oil preparation www.sunlightvitamins.com) preparations: polyvitamins (A, D, and C vitamin preparations)c 1 mL contains 400 IU; variable preparations that include glycerin and water; may also contain propylene glycol and/or polysorbate 80 Note that higher-dose oral preparations may be necessary for the treatment of those with rickets in the first few months of therapy or for patients with chronic diseases such as fat (cystic fibrosis) or patients chronically taking that interfere with vitamin D metabolism (such as antiseizure medications). a A study by Martinez et al162 showed that newborn and older infants preferred oil-based liquid preparations to alcohol-based preparations. b Single-drop preparation may be better tolerated in patients with oral aversion issues, but proper instruction regarding administration of these drops must be given to the parents or care provider, given the increased risk of toxicity, incorrect dosing, or accidental ingestion. c The cost of vitamin D–only preparations may be more than multivitamin preparations and could be an issue for health clinics that dispense vitamins to infants and children. The multivitamin preparation was the only preparation available until recently; therefore, there is a comfort among practitioners in dispensing to all age groups. dren and provide free vitamin supplements for them and ticularly in the winter months when mothers have mar- a vitamin D fact sheet for their mothers. Another recent ginal vitamin D status or are deficient, (3) that the study by Ziegler et al141 assessed the vitamin D status of amount of sunshine exposure necessary to maintain an 84 breastfeeding infants in Iowa (latitude 41°N). In the adequate 25-OH-D concentration in any given infant at 34 infants who received no supplemental vitamin D, 8 any point in time is not easy to determine, and (4) serum (23%) infants had a serum 25-OH-D concentration of 25-OH-D concentrations are maintained at Ͼ50 nmol/L Ͻ27 nmol/L at 280 days of age. Of these 8 low measure- in breastfed infants with 400 IU of vitamin D per day, the ments, 7 were made in the winter months (November following recommendation is made: A supplement of through April). Thus, at this time it is prudent to recom- 400 IU/day of vitamin D should begin within the first mend that all breastfed infants be given supplemental few days of life and continue throughout childhood. Any vitamin D3. breastfeeding infant, regardless of whether he or she is The 2003 AAP statement recommended supplements being supplemented with formula, should be supple- of 200 IU of vitamin D per day to all breastfed infants mented with 400 IU of vitamin D, because it is unlikely within the first 2 months of life, after breastfeeding was that a breastfed infant would consume1L(ϳ1 qt) of well established.1 This was in agreement with a 1997 formula per day, the amount that would supply 400 IU report from the Institute of Medicine.51 This report’s of vitamin D. recommendation of 200 IU/day was largely based on a study that showed that among breastfed infants in FORMS OF VITAMIN D SUPPLEMENTS northern China supplemented with 100 or 200 IU of There are 2 forms of vitamin D that have been used as 142 vitamin D per day, there were no cases of rickets. supplements: vitamin D2 (ergocalciferol, which is plant However, 17 of 47 infants and 11 of 37 infants receiving derived) and vitamin D3 (cholecalciferol, which is fish 100 or 200 IU of vitamin D per day, respectively, had derived). It has been shown that vitamin D3 has greater serum concentrations of 25-OH-D at Ͻ27 nmol/L. Al- efficacy in raising circulating 25-OH-D concentrations though corollary maternal serum concentrations were under certain physiological situations.144 Most fortified not measured, on the basis of vitamin D pharmacokinet- milk products and vitamin supplements now contain ics, maternal vitamin D status is assumed to have been vitamin D3. Vitamin D–only preparations are now avail- abnormally low, thereby preventing adequate transfer of able in the United States, in addition to the multivitamin vitamin D in human milk. When the breastfeeding liquids supplements, to provide the appropriate concen- mother has marginal vitamin D status or frank defi- trations of 400 IU/mL (see Table 2). Some also contain ciency, infant 25-OH-D concentrations are very low in 400 IU per drop, but such preparations must be pre- unsupplemented infants, particularly in the winter scribed with caution; explicit instruction and demonstra- months in latitudes further from the equator. It is clear tion of use are essential because of the greater potential that 25-OH-D concentrations of Ͼ50 nmol/L can be for a vitamin D overdose if several drops are adminis- maintained in exclusively breastfed infants with supple- tered at once. ments of 400 IU/day of vitamin D, which is the amount The new vitamin D–only preparations are particu- contained in 1 teaspoon of cod liver oil52,54 and for which larly appropriate for the breastfed infant who has no there is historic precedence of safety and prevention and need for multivitamin supplements. The cost of purchase treatment of rickets.5,6,143 and administration of vitamin D either alone or in com- Thus, given the evidence that (1) vitamin D defi- bination with vitamins A and C (as it is currently con- ciency can occur early in life, especially when pregnant stituted) is minimal. Pediatricians and other health care women are deficient, (2) 25-OH-D concentrations are professionals should work with the Special Supplemen- very low in unsupplemented breastfeeding infants, par- tal Nutrition Program for Women, Infants, and Children

1146 AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on October 2, 2021 clinics to make vitamin D supplements available for cantly lower 25-OH-D status than individuals who are breastfeeding infants. Current preparations, assuming not black. Although there have been no large series of correct administration of dosage by caregivers, place the adolescents with vitamin D–deficiency rickets, cases infant at little risk of overdosage and , continue to occur.15 although this must be considered. Care must be taken by The inverse relationship of increasing PTH with health care professionals to provide explicit instructions decreasing 25-OH-D concentrations has been demon- regarding the correct dosage and administration.145 Prep- strated in older children and adolescents.9,152 A study arations that contain higher concentrations of vitamin D of vitamin D insufficiency in 6- to 10-year-old pread- should only be prescribed in the setting of close surveil- olescent black children in Pittsburgh, PA, revealed lance of vitamin D status and for those who have such a that serum PTH concentrations decreased with increas- demonstrated requirement (eg, those who suffer from ing serum 25-OH-D concentrations and reached a pla- fat malabsorption or who must chronically take antisei- teau when the serum 25-OH-D concentration was Ն75 zure ). nmol/L.150 In Boston, MA, Gordon et al152 found that 24.1% of healthy teenagers in their cross-sectional co- FORMULA-FED INFANTS AND VITAMIN D SUPPLEMENTS hort were vitamin D deficient (25-OH-D concentration All infant formulas sold in the United States must have a Յ 37 nmol/L), of whom 4.6% were severely deficient minimum vitamin D concentration of 40 IU/100 kcal (25-OH-D concentration Յ 20 nmol/L) and 42% were (258 IU/L of a 20 kcal/oz formula) and a maximum vitamin D insufficient (25-OH-D concentration Յ 50 vitamin D3 concentration of 100 IU/100 kcal (666 IU/L nmol/L). There was an inverse correlation between se- of a 20 kcal/oz formula).146 All formulas sold in the rum 25-OH-D and PTH concentrations (R ϭϪ0.29). 147 United States have at least 400 IU/L of vitamin D3. Concentrations of 25-OH-D also were related to season, Because most formula-fed infants ingest nearly1Lor1 ethnicity, milk and juice consumption, BMI, and physi- qt of formula per day after the first month of life, they cal activity, which were independent predictors of vita- will achieve a vitamin D intake of 400 IU/day. As men- min D status. tioned earlier, infants who receive a mixture of human Similar results were found by Cheng et al89 in their milk and formula also should get a vitamin D supple- cohort of pubertal and prepubertal Finnish girls. These ment of 400 IU/day to ensure an adequate intake. As investigators also found a significantly lower cortical infants are weaned from breastfeeding and/or formula, volumetric bone-mineral density of the distal radius and intake of vitamin D–fortified milk should be encouraged tibial shaft in girls with vitamin D deficiency (as defined to provide at least 400 IU/day of vitamin D. Any infant by 25-OH-D concentrations Յ 25 nmol/L). These results who receives Ͻ1 L or 1 qt of formula per day needs an are supported by the work of Viljakainen et al58 in their alternative way to get 400 IU/day of vitamin D, such as study of 212 Finnish early-adolescent (aged 11–12 through vitamin supplements. years) girls who were randomly assigned to receive 0, 200, or 400 IU of vitamin D per day for 12 months. After VITAMIN D SUPPLEMENTS DURING LATER CHILDHOOD AND 1 year, bone-mineral augmentation of the femur was ADOLESCENCE 14.3% and 17.2% higher in the girls receiving 200 and As was mentioned earlier, there is active debate among 400 IU of vitamin D, respectively, compared with those vitamin D experts as to what constitutes vitamin D “suf- in the placebo group. ficiency,” “insufficiency,” and “deficiency” in adults and The extent of vitamin D deficiency has been sug- children as defined by 25-OH-D serum concentrations.‡ gested by reports from other regions of the world, Vitamin D deficiency is not limited to infancy and early including children and adolescents living in northern childhood but covers the life span, with periods of vul- Greece94 and Germany57 and adolescents in Beijing,153 nerability that mirror periods of accelerated growth or Turkey,88 Finland,58 and Ireland.95 With lower 25- physiologic change. In fact, vitamin D deficiency in older OH-D concentrations correlating with increased PTH children and adolescents continues to be reported world- concentrations, vitamin D deficiency could result in wide.§ Recent studies of vitamin D status have shown secondary hyperparathyroidism. This condition would that 16% to 54% of adolescents have serum 25-OH-D deplete the bone of mineral, especially during periods concentrations of Յ50 nmol/L.9,85–88,90,94,150–152 In 1 study of accelerated bone growth, and lead to long-term that used the adult definition of insufficiency of a serum detrimental effects. 25-OH-D concentration of Ͻ80 nmol/L, 73.1% of ado- In evaluating bone mineralization as a function of vita- lescents demonstrated values below this concentra- min D status in adolescents, several studies in the United tion.153 In examining the prevalence of vitamin D defi- States and Europe have demonstrated an unfavorable ciency in adolescents, studies across North America have effect of lower 25-OH-D concentrations on bone shown that serum 25-OH-D concentrations of Ͻ30 health.58,89,154,155 Adolescent girls with serum 25-OH-D con- nmol/L occur in as few as 1% to as many as 17% of centrations of Ͼ40 nmol/L have demonstrated increased adolescents, depending on the subjects themselves and radial, ulnar, and tibial bone-mineral densities,152 although the latitude and season of measurement.3,86,87,151,152 All of studies have demonstrated inconsistent findings in other these studies found black adolescents to have signifi- body sites.154 Additional studies are needed to identify the serum 25-OH-D status that promotes optimal bone health ‡Refs 6, 9, 56, 64, 66, 67, 94, 132, and 148–150. in older children and adolescents. §Refs 9, 57, 58, 85–89, 94–96, and 150–154. Although consuming 1 qt (32 oz) of vitamin D–forti-

PEDIATRICS Volume 122, Number 5, November 2008 1147 Downloaded from www.aappublications.org/news by guest on October 2, 2021 fied milk will provide 400 IU of vitamin D3 per day, it is 4. On the basis of the available evidence, serum 25- clear that in the adolescent population, the intake of OH-D concentrations in infants and children should vitamin D–fortified milk is much less.155–157 In the United be Ն50 nmol/L (20 ng/mL). States, milk intake decreased by 36% among adolescent 5. Children with increased risk of vitamin D deficiency, 156 girls from 1977–1978 to 1994–1998. Fortified cereals such as those with chronic fat malabsorption and 1 ( ⁄2-cup dry) and 1 egg (yolk) will each provide approx- those chronically taking antiseizure medications, may imately 40 IU of vitamin D3. Given the dietary practices continue to be vitamin D deficient despite an intake of many children and adolescents, a dietary intake of of 400 IU/day. Higher doses of vitamin D supplemen- 157 400 IU of vitamin D is difficult to achieve. Thus, for tation may be necessary to achieve normal vitamin D older children and adolescents, a daily multivitamin or status in these children, and this status should be vitamin D–only preparation containing 400 IU of vita- determined with laboratory tests (eg, for serum 25- min D would be warranted. Additional studies are OH-D and PTH concentrations and measures of bone- needed to evaluate what the optimal vitamin D status in mineral status). If a vitamin D supplement is pre- older children and adolescents is and whether this level scribed, 25-OH-D levels should be repeated at can be achieved consistently through diet and a vitamin 3-month intervals until normal levels have been D supplement of 400 IU/day. achieved. PTH and bone-mineral status should be Along with adequate vitamin D intake, dietary cal- monitored every 6 months until they have normal- cium intake to achieve optimal bone formation and ized. modeling must be ensured.87 A dietary history is essen- tial in assessing the adequacy of dietary intake for vari- 6. Pediatricians and other health care professionals ous vitamins, minerals, and nutrients, including vitamin should strive to make vitamin D supplements readily D and calcium.3,91 Children and adolescents at increased available to all children within their community, es- risk of developing rickets and vitamin D deficiency, in- pecially for those children most at risk. cluding those with increased skin pigmentation, de- COMMITTEE ON NUTRITION, 2007–2008 creased sunlight exposure, chronic diseases character- *Frank R. Greer, MD, Chairperson ized by fat malabsorption (cystic fibrosis, etc), and those Jatinder J. S. Bhatia, MD who require anticonvulsant medications (which induce Stephen R. Daniels, MD, PhD and other enzymes that may lead to Marcie B. Schneider, MD catabolism of vitamin D) may require even higher doses Janet Silverstein, MD than 400 IU/day of vitamin D.158–161 Nicolas Stettler, MD, MSCE Dan W. Thomas, MD

SUMMARY GUIDELINES LIAISONS To prevent rickets and vitamin D deficiency in healthy Donna Blum-Kemelor, MS, RD infants, children, and adolescents, a vitamin D intake of US Department of Agriculture at least 400 IU/day is recommended. To meet this intake Laurence Grummer-Strawn, PhD requirement, we make the following suggestions: Centers for Disease Control and Prevention Rear Admiral Van S. Hubbard, MD, PhD 1. Breastfed and partially breastfed infants should be National Institutes of Health supplemented with 400 IU/day of vitamin D begin- Valerie Marchand, MD ning in the first few days of life. Supplementation Canadian Paediatric Society should be continued unless the infant is weaned to at Benson M. Silverman, MD least 1 L/day or 1 qt/day of vitamin D–fortified formula US Food and Drug Administration or whole milk. Whole milk should not be used until after 12 months of age. In those children between 12 STAFF months and 2 years of age for whom or Debra L. Burrowes, MHA is a concern or who have a family history of obesity, dyslipidemia, or , the use SECTION ON BREASTFEEDING EXECUTIVE COMMITTEE, 2007–2008 of reduced-fat milk would be appropriate.163 Arthur J. Eidelman, MD, Policy Committee Chairperson 2. All nonbreastfed infants, as well as older children Ruth A. Lawrence, MD, Chairperson who are ingesting Ͻ1000 mL/day of vitamin D–for- Lori B. Feldman-Winter, MD tified formula or milk, should receive a vitamin D Jane A. Morton, MD supplement of 400 IU/day. Other dietary sources of Audrey J. Naylor, MD, DrPH vitamin D, such as fortified foods, may be included in Lawrence M. Noble, MD the daily intake of each child. Laura R. Viehmann, MD 3. Adolescents who do not obtain 400 IU of vitamin D *Carol L. Wagner, MD per day through vitamin D–fortified milk (100 IU per 8-oz serving) and vitamin D–fortified foods (such as LIAISONS fortified cereals and eggs [yolks]) should receive a Jatinder J. S. Bhatia, MD vitamin D supplement of 400 IU/day. Committee on Nutrition

1148 AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on October 2, 2021 Alice Lenihan, MPH, RD, LDN 20. Stearns G, Jeans PC, Vandecar V. The effect of vitamin D on National Association of WIC Directors linear growth in infancy. J Pediatr. 1936;9(1):1–10 Sharon Mass, MD 21. Pawley NJ, Bishop N. Prenatal and infant predictors of bone American College of Obstetrics and Gynecology health: the influence of vitamin D. Am J Clin Nutr. 2004;80(6 Julie Wood, MD suppl):1748S–1751S American Academy of Family Physicians 22. Molgaard C, Michaelsen KF. Vitamin D and bone health in early life. Proc Natl Acad Sci U S A. 2003;62(4):823–828 23. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M, STAFF on behalf of the Drug and Therapeutics Committee of the Lauren Barone, MPH Lawson Wilkins Pediatric Endocrine Society. Vitamin D defi- ciency in children and its management: review of current *Lead Authors knowledge and recommendations. Pediatrics. 2008;122(2): 398–417 REFERENCES 24. Holick MF. Vitamin D: Importance in the prevention of can- 1. Gartner LM, Greer FR; American Academy of Pediatrics, Sec- cers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin tion on Breastfeeding Medicine and Committee on Nutrition. Nutr. 2004;79(3):362–371 Prevention of rickets and vitamin D deficiency: new guide- 25. Hathcock JN, Shao A, Vieth R, Heaney RP. Risk assessment lines for vitamin D intake. Pediatrics. 2003;111(4):908–910 for vitamin D. Am J Clin Nutr. 2007;85(1):6–18 2. McCollum EV, Simmonds N, Becket JE, Shipley PG. Studies 26. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3): on experimental rickets. XXI. An experimental demonstration 266–281 of the existence of a vitamin, which promotes calcium depo- 27. Webb AR. Who, what, where and when: influences on cuta- sition. J Biol Chem. 1922;53(8):219–312 neous vitamin D synthesis. Prog Biophys Mol Biol. 2006;92(1): 3. Moore C, Murphy MM, Keast DR, Holick M. Vitamin D intake 17–25 in the United States. J Am Diet Assoc. 2004;104(6):980–983 28. Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray 4. Thacher TD, Fischer PR, Strand MA, Pettifor JM. Nutritional TJ, Ebers GC. Timing of birth and risk of multiple sclerosis: rickets around the world: causes and future directions. Ann population based study. BMJ. 2005;330(7483):120 Trop Paediatr. 2006;26(1):1–16 29. Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, 5. Park EA. The therapy of rickets. JAMA. 1940;115:370–379 Gilkeson GS. Vitamin D deficiency in systemic lupus erythem- 6. Rajakumar K, Thomas SB. Reemerging nutritional rickets: a atosus. Autoimmun Rev. 2006;5(2):114–117 historical perspective. Arch Pediatr Adolesc Med. 2005;159(4): 30. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw 335–341 EK, Gorham ED. Serum 25(OH)D and colon cancer: eight- 7. Mylott BM, Kump T, Bolton ML, Greenbaum LA. Rickets in year prospective study. Lancet. 1989;2(8673):1176–1178 the Dairy State. WMJ. 2004;103(5):84–87 31. Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of 8. Pettifor JM. Nutritional rickets: deficiency of vitamin D, cal- predictors of vitamin D status and cancer incidence and mor- cium, or both? Am J Clin Nutr. 2004;80(6 suppl):1725S–1729S tality in men. J Natl Cancer Inst. 2006;98(7):451–459 9. Pettifor JM. Rickets and vitamin D deficiency in children and 32. Institute of Medicine. Calcium, vitamin D, and magnesium. adolescents. Endocrinol Metab Clin North Am 2005;34(3): In: Subcommittee on Nutritional Status and Weight Gain 537–553, vii During Pregnancy, ed. Nutrition During Pregnancy. Washing- 10. Kreiter SR, Schwartz RP, Kirkman HN, Charlton PA, Caliko- ton, DC: National Academy Press; 1990:318–335 glu AS, Davenport ML. Nutritional rickets in African Ameri- 33. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a can breast-fed infants. J Pediatr. 2000;137(2):153–157 vitamin D-mediated human antimicrobial response. Science. 11. Pugliese MT, Blumberg DL, Hludzinski J, Kay S. Nutritional 2006;311(5768):1770–1773 rickets in suburbia. J Am Coll Nutr. 1998;17(6):637–641 12. Sills IN, Skuza KA, Horlick MN, Schwartz MS, Rapaport R. 34. Rehman PK. Sub-clinical rickets and recurrent infection. J Vitamin D deficiency rickets: reports of its demise are exag- Trop Pediatr. 1994;40(1):58 gerated. Clin Pediatr (Phila). 1994;33(8):491–493 35. Martineau AR, Wilkinson RJ, Wilkinson KA, et al. A single 13. Ward LM. Vitamin D deficiency in the 21st century: a persis- dose of vitamin D enhances immunity to mycobacteria. Am J tent problem among Canadian infants and mothers. CMAJ. Respir Crit Care Med. 2007;176(2):208–213 2005;172(6):769–770 36. Hayes CE. Vitamin D: a natural inhibitor of multiple sclerosis. 14. Weisberg P, Scanlon K, Li R, Cogswell ME. Nutritional rickets Proc Nutr Soc. 2000;59(4):531–535 among children in the United States: review of cases reported 37. Munger KL, Zhang SM, O’Reilly E, et al. Vitamin D intake and between 1986 and 2003. Am J Clin Nutr. 2004;80(6 suppl): incidence of multiple sclerosis. Neurology. 2004;62(1):60–65 1697S–1705S 38. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag 15. Schnadower D, Agarwal C, Oberfield SE, Fennoy I, Pusic M. KG. Vitamin D intake is inversely associated with rheumatoid Hypocalcemic seizures and secondary bilateral femoral frac- arthritis: results from the Iowa Women’s Health Study. Ar- tures in an adolescent with primary vitamin D deficiency. thritis Rheum. 2004;50(1):72–77 Pediatrics. 2006;118(5):2226–2230 39. Garland FC, Garland CF, Gorham ED, Young JE. Geographic 16. Ladhani S, Srinivasan L, Buchanan C, Allgrove J. Presentation variation in breast cancer mortality in the United States: a of vitamin D deficiency. Arch Dis Child. 2004;89(8):781–784 hypothesis involving exposure to solar radiation. Prev Med. 17. Hatun S, Ozkan B, Orbak Z, et al. Vitamin D deficiency in 1990;19(6):614–622 early infancy. J Nutr. 2005;135(2):279–282 40. Lefkowitz ES, Garland CF. Sunlight, vitamin D, and ovarian 18. Binet A, Kooh SW. Persistence of vitamin D-deficiency rickets cancer mortality rates in US women. Int J Epidemiol. 1994; in Toronto in the 1990s. Can J Public Health. 1996;87(4): 23(6):1133–1136 227–230 41. Grant WB. An ecologic study of dietary and solar -B 19. Najada AS, Habashneh MS, Khader M. The frequency of links to breast carcinoma mortality rates. Cancer. 2002;94(1): nutritional rickets among hospitalized infants and its relation 272–281 to respiratory diseases. J Trop Pediatr. 2004;50(6):364–368 42. Grant WB. An estimate of premature cancer mortality in the

PEDIATRICS Volume 122, Number 5, November 2008 1149 Downloaded from www.aappublications.org/news by guest on October 2, 2021 US due to inadequate doses of solar ultraviolet-B radiation. 63. El-Hajj Fuleihan E, Nabulsi M, Tamim H, et al. Effect of Cancer. 2002;94(6):1867–1875 vitamin D replacement on musculoskeletal parameters in 43. Chiu K, Chu A, Go VL, Soad MF. Hypovitaminosis D is asso- school children: a randomized controlled trial. J Clin Endocri- ciated with insulin resistance and beta cell dysfunction. Am J nol Metab. 2006;91(2):405–412 Clin Nutr. 2004;79(5):820–825 64. Vieth R, Bischoff-Ferrari H, Boucher BJ, et al. The urgent 44. Pittas AG, Dawson-Hughes B, Li T, et al. Vitamin D and need to recommend an intake of vitamin D that is effective calcium intake in relation to type 2 diabetes in women. Dia- [published correction appears in Am J Clin Nutr. 2007;86(3): betes Care. 2006;29(3):650–656 809]. Am J Clin Nutr. 2007;85(3):649–650 45. Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of 65. Hollis BW, Wagner CL, Drezner MK, Binkley NC. Circulating

serum vitamin D and the among U.S. vitamin D3 and 25-hydroxyvitamin D in humans: an impor- adults. Diabetes Care. 2005;28(5):1228–1230 tant tool to define adequate nutritional vitamin D status. J 46. The EURODIAB Substudy 2 Study Group. Vitamin D supple- Steroid Biochem Mol Biol. 2007;103(3–5):631–634 ment in early childhood and risk for type 1 (insulin- 66. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative dependent) diabetes mellitus. Diabetologia. 1999;42(1):51–54 of vitamin sufficiency: implications for establishing a new 47. Hyppo¨nen E, Laara E, Reunanen A, Jarvelin MR, Virtanen effective DRI for vitamin D. J Nutr. 2005;135(2):317–322 SM. Intake of vitamin D and risk of type 1 diabetes: a birth- 67. Hollis BW, Wagner CL, Kratz A, Sluss PM, Lewandrowski KB. cohort study. Lancet. 2001;358(9292):1500–1503 Normal serum vitamin D levels. Correspondence. N Engl 48. Harris SS. Vitamin D in type 1 diabetes prevention. J Nutr. J Med. 2005;352(5):515–516 2005;135(2):323–325 68. Heaney RP, Dowell MS, Hale CA, Bendich A. Calcium absorp- 49. Shehadeh N, Shamir R, Berant M, Etzioni A. Insulin in hu- tion varies within the reference range for serum 25- man milk and the prevention of type 1 diabetes. Pediatr Dia- hydroxyvitamin D. J Am Coll Nutr. 2003;22(2):142–146 betes. 2001;2(4):175–177 69. Need AG. markers in vitamin D insufficiency. 50. Fronczak CM, Baron AE, Chase HP, et al. In utero dietary Clin Chim Acta. 2006;368(1–2):48–52 exposures and risk of islet autoimmunity in children. Diabetes 70. Greer FR, Marshall S. Bone mineral content, serum vitamin D Care. 2003;26(12):3237–3242 metabolite concentrations and ultraviolet B light exposure in 51. Standing Committee on the Scientific Evaluation of Dietary infants fed human milk with and without vitamin D2 supple- Reference Intakes Food and Nutrition Board, Institute of ments. J Pediatr. 1989;114(2):204–212 Medicine. Calcium, , magnesium, vitamin D and 71. Hollis BW, Wagner CL. Assessment of dietary vitamin D re- fluoride. In: Dietary Reference Intakes. Washington, DC: Na- quirements during pregnancy and lactation. Am J Clin Nutr. tional Academy Press; 1997:250–287 2004;79(5):717–726 52. Marriott W, Jeans P. Infant Nutrition: A Textbook of Infant 72. Basile LA, Taylor SN, Wagner CL, Horst RL, Hollis BW. The Feeding for Students and Practitioners of Medicine. 3rd ed. St effect of high-dose vitamin D supplementation on serum vi- Louis, MO: Mosby; 1941 tamin D levels and milk calcium concentration in lactating 53. American Academy of Pediatrics, Committee on Nutrition. women and their infants. Breastfeed Med. 2006;1(1):32–35 The prophylactic requirement and the toxicity of vitamin D. 73. Wagner CL, Hulsey TC, Fanning D, Ebeling M, Hollis BW. 1963;31(3):512–525 High dose vitamin D supplementation in a cohort of breast- 54. Davison W. The Compleat Pediatrician: Practical, Diagnostic, Ther- 3 feeding mothers and their infants: a six-month follow-up pilot apeutic and Preventive Pediatrics. For the Use of Medical Students, study. Breastfeed Med. 2006;1(2):59–70 Interns, General Practitioners, and Pediatricians. Durham, NC: 74. Hollis BW, Wagner CL. Vitamin D requirements during Duke University Press; 1943 lactation: High-dose maternal supplementation as therapy to 55. Aldrich C, Aldrich M. Babies Are Human Beings: An Interpreta- tion of Growth. New York, NY: Macmillan Company; 1938 prevent hypovitaminosis D in both mother and nursing in- 56. Roth DE, Martz P, Yeo R, Prosser C, Bell M, Jones AB. Are fant. Am J Clin Nutr. 2004;80(6 suppl):1752S–1758S national vitamin D guidelines sufficient to maintain adequate 75. Holick MF, MacLaughlin JA, Clark MB, et al. Photosynthesis blood levels in children? Can J Public Health. 2005;96(6): of vitamin D3 in human skin and its physiologic conse- 443–449 quences. Science. 1980;210(4466):203–205 57. Sichert-Hellert W, Wenz G, Kersting M. Vitamin intakes from 76. Kimlin MC, Schallhorn KA. Estimations of the human “vita- supplements and fortified food in German children and min D” UV exposure in the USA. Photochem Photobiol Sci. adolescents: results from the DONALD study. J Nutr. 2006; 2004;3(11–12):1067–1070 136(5):1329–1333 77. Matsuoka LY, Wortsman J, Haddad JG, Kolm P, Hollis BW. 58. Viljakainen HT, Natri AM, Ka¨rkka¨inen MM, et al. A positive Racial pigmentation and the cutaneous synthesis of vitamin dose-response effect of vitamin D supplementation on site- D. Arch Dermatol. 1991;127(4):536–538 specific bone mineral augmentation in adolescent girls: a dou- 78. Matsuoka LY, Wortsman J, Hollis BW. Suntanning and cuta- ble-blinded randomized placebo-controlled 1-year interven- neous synthesis of vitamin D3. J Lab Clin Med. 1990;116(1): tion. J Bone Miner Res. 2006;21(6):836–844 87–90 59. Canadian Paediatric Society, Health Canada; Dietitians of 79. Matsuoka LY, Wortsman J, Dannenberg MJ, Hollis BW, Lu Z, Canada. Breastfeeding and Vitamin D. Ottawa, Ontario, Canada: Holick MF. Clothing prevents ultraviolet-B-radiation- Canadian Paediatric Society; 2003 dependent photosynthesis of vitamin D3. J Clin Endocrinol 60. Dobrescu MO, Garcia AC, Robert M. Rickets. CMAJ. 2006; Metab. 1992;75(4):1099–1103 174(12):1710 80. Matsuoka LY, Wortsman J, Hollis BW. Use of topical sun-

61. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, screen for the evaluation of regional synthesis of vitamin D3. Dawson-Hughes B. Estimation of optimal serum concentra- J Am Acad Dermatol. 1990;22(5 pt 1):772–775 tions of 25-hydroxyvitamin D for multiple health outcomes. 81. Ala-Houhala M. 25(OH)D levels during breast-feeding with or Am J Clin Nutr. 2006;84(1):18–28 without maternal or infantile supplementation of vitamin D. 62. Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier J Pediatr Gastroenterol Nutr. 1985;4(2):220–226 PJ, Vieth R. Estimates of vitamin D status. Osteoporosis Int. 82. US Environmental Protection Agency. Report to Congress on 2005;16(7):713–716 Indoor Air Quality. Volume II: Assessment and Control of Indoor Air

1150 AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on October 2, 2021 Pollution: US Environmental Protection Agency: Washington, and non-melanocytic skin cancer. Med J Aust. 1990;152(2): DC; 1989. Report EPA 400-1-89-001C 62–66 83. Nesby-O’Dell S, Scanlon KS, Cogswell ME, et al. Hypovita- 102. Autier P, Dore JF. Influence of sun exposures during child- minosis D prevalence and determinants among African Amer- hood and during adulthood on melanoma risk. EPIMEL and ican and white women of reproductive age: Third National EORTC Melanoma Cooperative Group. Int J Cancer. 1998; Health and Nutrition Examination Survey: 1988–1994. Am J 77(4):533–537 Clin Nutr. 2002;76(1):187–192 103. Westerdahl J, Olsson H, Ingvar C. At what age do 84. Scanlon KS. Vitamin D expert panel meeting, October 11–12, episodes play a crucial role for the development of malignant Atlanta, Georgia: final report. Available at: www.cdc.gov/ melanoma. Eur J Cancer. 1994;30A(11):1647–1654 nccdphp/dnpa/nutrition/pdf/VitaminDExpertPanelMeeting. 104. Gilchrest BA, Eller MS, Geller AC, Yaar M. The pathogenesis pdf. Accessed July 24, 2008 of melanoma induced by ultraviolet radiation. N Engl J Med. 85. Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahy- 1999;340(17):1341–1348 oun NR. Serum 25-hydroxyvitamin D status of adolescents 105. American Academy of Pediatrics, Committee on Environ- and adults in two seasonal subpopulations from NHANES III. mental Health. Ultraviolet light: a hazard to children. Pediat- Bone. 2002;30(5):771–777 rics. 1999;104(2 pt 1):328–333 86. Harkness LS, Cromer BA. Vitamin D deficiency in adolescent 106. Lucas R, Ponsonby AL. Considering the potential benefits as females. J Adolesc Health. 2005;37(1):75 well as adverse effects of sun exposure: can all the potential 87. Harkness LS, Bonny AE. Calcium and vitamin D status in the benefits be provided by oral vitamin D supplementation? Prog adolescent: key roles for bone, body weight, glucose toler- Biophys Mol Biol. 2006;92(1):140–149 ance, and estrogen biosynthesis. J Pediatr Adolesc Gynecol. 107. Mahomed K, Gulmezoglu AM. Vitamin D supplementation in 2005;18(5):305–311 pregnancy [Cochrane review]. In: The Cochrane Library. Ox- 88. Olmez D, Bober E, Buyukgebiz A, Cimrin D. The frequency of ford, United Kingdom: Update Software; 2002 vitamin D insufficiency in healthy female adolescents. Acta 108. Mallet E, Gugi B, Brunelle P, Henocq A, Basuyau JP, Lemeur Paediatr. 2006;95(10):1266–1269 H. Vitamin D supplementation in pregnancy: a controlled trial 89. Cheng S, Tylavsky F, Kroger H, et al. Association of low of two methods. Obstet Gynecol. 1986;68(3):300–304 25-hydroxyvitamin D concentrations with elevated parathy- 109. Brooke OG, Brown IRF, Bone CDM, et al. Vitamin D supple- roid hormone concentrations and low cortical in ments in pregnant Asian women: effects on calcium status early pubertal and prepubertal Finnish girls. Am J Clin Nutr. and fetal growth. Br Med J. 1980;280(6216):751–754 2003;78(3):485–492 110. Maxwell JD, Ang L, Brooke OG, Brown IRF. Vitamin D 90. Tylavsky FA, Ryder KA, Lyytika¨inen A, Cheng S. Vitamin D, supplements enhance weight gain and nutritional status in parathyroid hormone, and bone mass in adolescents. J Nutr. pregnant Asians. Br J Obstet Gynaecol. 1981;88(10):987–991 2005;135(11):2735S–2738S 111. Brooke OG, Butters F, Wood C. Intrauterine vitamin D nu- 91. DeBar LL, Ritenbaugh C, Aickin M, et al. A health plan-based trition and postnatal growth in Asian infants. Br Med J (Clin lifestyle intervention increases bone mineral density in ado- Res Ed). 1981;283(6298):1024 lescent girls. Arch Pediatr Adolesc Med. 2006;160(12): 112. Cockburn F, Belton NR, Purvis RJ, et al. Maternal vitamin D 1269–1276 intake and mineral metabolism in mothers and their newborn 92. El-Hajj Fuleihan GH, Nabulsi M, Choucair M, et al. Hypovi- infants. Br Med J. 1980;281(6232):11–14 taminosis D in healthy schoolchildren. Pediatrics. 2001;107(4). 113. Delvin EE, Salle L, Glorieux FH, Adeleine P, David LS. Vita- Available at: www.pediatrics.org/cgi/content/full/107/4/e53 min D supplementation during pregnancy: effect on neonatal 93. Marwaha RK, Tandon N, Reddy DR, et al. Vitamin D and calcium homeostasis. J Pediatr. 1986;109(2):328–334 bone mineral density status of healthy schoolchildren in 114. Vieth R, Chan PCR, MacFarlane GD. Efficacy and safety of

northern India. Am J Clin Nutr. 2005;82(2):477–482 vitamin D3 intake exceeding the lowest observed adverse 94. Lapatsanis D, Moulas A, Cholevas V, Soukakos P, Papadopou- effect level (LOAEL). Am J Clin Nutr. 2001;73(2):288–294 lou Z, Challa A. Vitamin D: a necessity for children and 115. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. adolescents in Greece. Calcif Tissue Int. 2005;77(6):348–355 Human serum 25-hydroxycholecalciferol response to ex- 95. Hill TR, Flynn A, Kiely M, Cashman KD. Prevalence of sub- tended oral dosing with cholecalciferol. Am J Clin Nutr. 2003; optimal vitamin D status in young, adult and elderly Irish 77(1):204–210 subjects. Ir Med J. 2006;99(2):48–49 116. van der Meer IM, Karamali NS, Boeke AJ. High prevalence of 96. Primary vitamin D deficiency in children. Drug Ther Bull. vitamin D deficiency in pregnant non-Western women in the 2006;44(2):12–16 Hague, Netherlands. Am J Clin Nutr. 2006;84(2):350–353 97. Grant WB, Garland C, Holick MF. Comparisons of estimated 117. Bouillon R, Van Baelen H, DeMoor D. 25-Hydroxy-vitamin D economic burdens due to insufficient solar ultraviolet irradi- and its binding protein in maternal and cord serum. J Clin ance and vitamin D and excess solar UV irradiance for the Endocrinol Metab. 1977;45(4):679–684 United States. Photochem Photobiol. 2005;81(6):1276–1286 118. Bouillon R, Van Assche FA, Van Baelen H, Heyns W, DeMoor 98. Reichrath J. The challenge resulting from positive and nega- P. Influence of the vitamin D-binding protein on serum con-

tive effects of sunlight: how much solar UV exposure is ap- centrations of 1,25(OH)2D. J Clin Invest. 1981;67(3):589–596 propriate to balance between risks of vitamin D deficiency 119. Markestad T, Aksnes L, Ulstein M, Aarskog D. 25-Hydroxyvi-

and skin cancer? Prog Biophys Mol Biol. 2006;92(1):9–16 tamin D and 1,25-dihydroxy vitamin D of D2 and D3 origin in

99. Wolpowitz D, Gilchrest BA. The vitamin D questions: how maternal and umbilical cord serum after vitamin D2 supple- much do you need and how should you get it? J Am Acad mentation in human pregnancy. Am J Clin Nutr. 1984;40(5): Dermatol. 2006;54(2):301–317 1057–1063 100. National Coalition for Skin Cancer Prevention. The National 120. Hollis BW, Pittard WB. Evaluation of the total fetomaternal Forum for Skin Cancer Prevention in Health, Physical Education, vitamin D relationships at term: evidence for racial differ- Recreation and Youth Sports. Reston, VA: American Association ences. J Clin Endocrinol Metab. 1984;59(4):652–657 for Health Education; 1998 121. Hollis BW, Wagner CL. Nutritional vitamin D status during 101. Marks R, Jolley D, Lectsas S, Foley P. The role of childhood pregnancy: reasons for concern. CMAJ. 2006;174(9): exposure to sunlight in the development of solar keratoses 1287–1290

PEDIATRICS Volume 122, Number 5, November 2008 1151 Downloaded from www.aappublications.org/news by guest on October 2, 2021 122. Mannion C, Gray-Donald K, Koski K. Association of low 144. Armas L, Hollis BW, Heaney RP. Vitamin D2 is much less

intake of milk and vitamin D during pregnancy with de- effective than vitamin D3 in humans. J Clin Endocrinol Metab. creased birth weight. CMAJ. 2006;174(9):1273–1277 2004;89(11):5387–5391 123. Javaid MK, Crozier SR, Harvey NC, et al. Maternal vitamin D 145. Barrueto F Jr, Wang-Flores HH, Howland MA, Hoffman RS, status during pregnancy and childhood bone mass at age 9 Nelson LS. Acute vitamin D intoxication in a child. Pediatrics. years: a longitudinal study [published correction appears in 2005;116(3). Available at: www.pediatrics.org/cgi/content/ Lancet. 2006;367(9521):1486]. Lancet. 2006;367(9504):36–43 full/116/3/e453 124. Hyppo¨nen E. Vitamin D for the prevention of preeclampsia? 146. Assessment of nutrient requirements for infant formulas. J A hypothesis. Nutr Rev. 2005;63(7):225–232 Nutr. 1998;128(11 suppl):i–iv, 2059S–2293S 125. Moncrieff M, Fadahunsi TO. Congenital rickets due to mater- 147. Tsang R, Zlotkin S, Nichols B, Hansen J. Nutrition During nal vitamin D deficiency. Arch Dis Child. 1974;49(10): Infancy: Principles and Practice. 2nd ed. Cincinnati, OH: Digital 810–811 Education Publishing; 1997 126. Specker BL, Tsang RC, Hollis BW. Effect of race and diet on 148. Hanley DA, Davison KS. Vitamin D insufficiency in North human milk vitamin D and 25(OH)D. Am J Dis Child. 1985; America. J Nutr. 2005:135(2)332–337 139(11):1134–1137 149. Whiting SJ, Calvo MS. Overview of the proceedings from 127. Cancela L, LeBoulch N, Miravet L. Relationship between the Experimental Biology 2005 Symposium: Optimizing Vitamin vitamin D content of maternal milk and the vitamin D status D Intake for Populations With Special Needs: Barriers to of nursing women and breastfed infants. J Endocrinol. 1986; Effective Food Fortification and Supplementation. J Nutr. 110(1):43–50 2006;136(4):1114–1116 128. Hollis BW, Roos B, Draper HH, Lambert PW. Vitamin D and 150. Rajakumar K, Fernstrom JD, Janosky JE, Greenspan SL. Vi- its metabolites in human and bovine milk. J Nutr. 1981; tamin D insufficiency in preadolescent African-American 111(7):1240–1248 children. Clin Pediatr (Phila). 2005;44(8):683–692 129. Greer FR, Hollis BW, Cripps DJ, Tsang RC. Effects of maternal 151. Lanou AJ, Berkow SE, Barnard ND. Calcium, dairy products, ultraviolet B irradiation on vitamin D content of human milk. and bone health in children and young adults: a reevaluation J Pediatr. 1984;105(3):431–433 of the evidence. Pediatrics. 2005;115(3):736–743 130. Daaboul J, Sanderson S, Kristensen K, Kitson H. Vitamin D 152. Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. deficiency in pregnant and breast-feeding women and their Prevalence of vitamin D deficiency among healthy adoles- infants. J Perinatol. 1997;17(1):10–14 cents. Arch Pediatr Adolesc Med. 2004;158(6):531–537 131. Kreiter S. The reemergence of vitamin D deficiency rickets: 153. Du X, Greenfield H, Fraser DR, Ge K, Trube A, Wang Y. the need for vitamin D supplementation. AMB News Views Vitamin D deficiency and associated factors in adolescent girls Newsl. 2001;7:1–5 in Beijing. Am J Clin Nutr. 2001;74(4):494–500 132. Basile LA, Taylor SN, Wagner CL, Quinones L, Hollis BW. 154. Abrams SA, Griffin IJ, Hawthorne KM, Gunn SK, Gundberg Neonatal vitamin D status at birth at latitude 32 degrees 72Ј: CM, Carpenter TO. Relationships among vitamin D levels, evidence of deficiency. J Perinatol. 2007;27(9):568–571 parathyroid hormone, and calcium absorption in young ado- 133. Saadi H, Dawodu A, Afandi B, Zayed R, Benedict S, lescents. J Clin Endocrinol Metab. 2005;90(10):5576–5581 Nagelkerke N. Efficacy of daily and monthly high-dose calcif- 155. Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson-Hughes B. erol in vitamin D-deficient nulliparous and lactating women. Positive association between 25(OH)D levels and bone min- Am J Clin Nutr. 2007;85(6):1565–1571 eral density: a population-based study of younger and older 134. Ala-Houhala M, Koskinen T, Terho A, Koivula T, Visakorpi J. Maternal compared with infant vitamin D supplementation. adults. Am J Med. 2004;116(9):634–639 Arch Dis Child. 1986;61(12):1159–1163 156. Greer FR, Krebs NF, American Academy of Pediatrics, Com- 135. Kramer M, Kakuma R. The Optimal Duration of Exclusive mittee on Nutrition. Optimizing bone health and calcium Breastfeeding: A Systematic Review. Geneva, Switzerland: World intakes of infants, children, and adolescents. Pediatrics. 2006; Health Organization; 2002 117:578–585 136. Gartner LM, Morton J, Lawrence RA, et al. Breastfeeding and 157. Bowman SA. Beverage choices of young females: changes the use of human milk. Pediatrics. 2005;115(2):496–506 and impact on nutrient intakes. J Am Diet Assoc. 2002;102: 137. Chantry C, Howard C, Auinger P. Full breastfeeding duration 1234 and associated decrease in respiratory tract Infection in US 158. Fisher JO, Mitchell DC, Smiciklas-Wright H, Mannino ML, Children. Pediatrics. 2006;117(2):425–432 Birch LL. Meeting calcium recommendations during middle 138. Greer FR. Issues in establishing vitamin D recommendations childhood reflects mother-daughter beverage choices and for infants and children. Am J Clin Nutr. 2004;80(6 suppl): predicts bone mineral status. Am J Clin Nutr. 2004;79: 1759S–1762S 698–706 139. Gessner BD, deSchweinitz E, Petersen KM, Lewandowski C. 159. Aris RM, Merkel PA, Bachrach LK, et al. Guide to bone health Nutritional rickets among breast-fed black and Alaska Native and disease in cystic fibrosis. J Clin Endocrinol Metab. 2005;90: children. Alaska Med. 1997;39(3):72–74, 87 1888–1896 140. Gessner BD, Plotnik J, Muth PT. 25-Hydroxyvitamin D levels 160. Mikati MA, Dib L, Yamout B, Sawaya R, Rahi AC, Fuleihan among healthy children in Alaska. J Pediatr. 2003;143(4): Gel-H. Two randomized vitamin D trials in ambulatory pa- 434–437 tients on anticonvulsants. Impact on bone. Neurology. 2006; 141. Ziegler EE, Hollis BW, Nelson SE, Jeter JM. Vitamin D defi- 67:2005–2014 ciency in breastfed infants in Iowa. Pediatrics. 2006;118(2): 161. Valsamis HA, Arora SK, Labban B, McFarlane SI. Antiepilep- 603–610 tic drugs and bone metabolism. Nutr Metab (Lond). 2006;3:36 142. Ho ML, Yen HC, Tsang RC, Specker BL, Chen XC, Nichols BL. 162. Martı´nezJ, Bartoli F, Recaldini E, Lavanchy L, Bianchetti M. Randomized study of sunshine exposure and serum 25 A taste comparison of two different liquid colecalciferol (vi-

(OH)D in breast-fed infants in Beijing, China. J Pediatr. 1985; tamin D3) preparations in healthy newborns and infants. Clin 107(6):928–931 Drug Investig. 2006;26(11):663–665 143. Mozolowski W. Jedrzej Sniadecki (1768–1883) on the cure of 163. Daniels SR, Greer FR. Lipid screening and cardiovascular rickets. Nature. 1939;143(January 21):121 health in childhood. Pediatrics. 2008;122(1):198–208

1152 AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on October 2, 2021 Prevention of Rickets and in Infants, Children, and Adolescents Carol L. Wagner and Frank R. Greer Pediatrics 2008;122;1142 DOI: 10.1542/peds.2008-1862

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/122/5/1142 References This article cites 145 articles, 56 of which you can access for free at: http://pediatrics.aappublications.org/content/122/5/1142#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Committee on Nutrition http://www.aappublications.org/cgi/collection/committee_on_nutritio n Endocrinology http://www.aappublications.org/cgi/collection/endocrinology_sub Metabolic Disorders http://www.aappublications.org/cgi/collection/metabolic_disorders_s ub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 2, 2021 Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents Carol L. Wagner and Frank R. Greer Pediatrics 2008;122;1142 DOI: 10.1542/peds.2008-1862

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/122/5/1142

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on October 2, 2021